The functioning of neuronal circuits in the cerebral cortex underlies our highest cognitive and perceptual abilities, yet the rules underlying the formation of specific connections among cortical neurons are largely unknown. During development, proliferating cells of the cortical neuroepithelium generate young neurons that migrate away from their site of origin into distinct positions within the cortex, where they assemble into the layers and columns that form the structural basis of cortical processing. Defects in the production and migration of cerebral cortical neurons have fundamental implications for mental health, particularly since migration disorders have been implicated in schizophrenia and bipolar affective illness. The goal of this research is to explore the cellular and molecular processes by which neural progenitor cells in the mammalian cerebral cortex produce young neurons and to study how these neurons migrate to appropriate positions within the brain. Four specific issues are under study: (1) What cell types are generated from symmetric and asymmetric divisions? We will ascertain the fates of cells generated from different types of divisions by imaging progenitors in the ventricular zone, then staining daughter cells with markers that distinguish postmitotic neurons and mitotically active cells. (2) Do extrinsic factors regulate the cleavage orientations of mitotic progenitor cells? We will examine the possible role of secreted growth factors on the proliferation, differentiation, and cleavage orientation of progenitors in cultured slices. (3) What proteins are localized asymmetrically in mitotic progenitor cells? We will employ biochemical techniques to assess the subcellular distribution of known proteins and to identify novel proteins that are localized asymmetrically. (4) What is the fate of tangentially migrating neurons in the developing cerebral cortex? We will track the numbers and the nature of nonradially migrating neurons in vivo by making small injections of 3H-thymidine at a point within the ventricular zone, then use markers for different neuronal phenotypes to assess their migration pathways. Collectively, the results of these experiments will provide us with information about the cellular and molecular mechanisms of neurogenesis and neuronal migration in the developing cerebral cortex. Such studies of normal development are likely to provide important insights into the ontogeny of developmental brain disorders in humans and, ultimately, to generate strategies for the appropriate treatment of such disorders.